The present invention relates to treating autism and, more specifically, to treating autism by increasing expression and/or activity of exorphin cleaving gene products. The present invention also includes the use of phytase and like substances and formulations containing enzymatic and phytase-like compounds for treating autism.
Autism may be defined as a condition, usually present from childhood, that is characterized by self-absorption, a reduced ability to respond to or communicate with the outside world and behavioral dysfunction. An autistic individual may suffer from several maladies with the accumulated symptoms being categorized as autism spectrum disorders, referred to in the field as autism or ASD. Symptoms of autism include stimming, reduced eye contact, perseveration (repeating same activity for long periods), poor communication and social skills and heightened sound sensitivity, amongst others.
It has been estimated that from 1 in 2,000 to 1 in 300 persons suffer from autism with an initial manifestation of symptoms by age three. It is of interest to note that the overall percentage of persons exhibiting symptoms of autism is increasing, in some instances dramatically. As discussed below, this rise may be due in part to an increase in the percentage of persons receiving childhood vaccinations. Males are more likely to suffer from autism than females.
There are several theories related to the initial and continued cause(s) of autism. One theory relates to infection or inflammation in the stomach and/or intestines early in life and maladaptation of the immune system and other tissues to this inflammation.
Historically, the immune system has been thought to develop early in life through education of the cellular components within the thymus (T-cells) and spleen (B-cells). There, the various cells are trained to recognize self vs. non-self antigens and to take the appropriate action, or lack thereof, in response to any exposure. In the last decade, however, a new class of immune cells has been intensively studied. These cells never xe2x80x9cseexe2x80x9d the thymus or spleen and are educated solely in the intestinal tissues from which they arise. These intraepithelial lymphocytes (IEL), or xe2x80x9cintestinalxe2x80x9d epithelial lymphocytes, are an athymically derived T-cell subset expressing the xcex3xcex4 TCR-CD3 complex along with CD8. The xcex3xcex4 T cells in the epithelial tissues do not circulate as their xcex1xcex2 T cell (thymically derived) relatives do.
Though the subject of much speculation, the IELs are thought to be a primordial immune system and the first to function in life. IELs have been shown to bind to mycobacterial antigens that are protease resistant and appear to have been selected to respond quickly to unique immune challenges. Since the mycobacterial antigens are protease resistant proteins, immune cells responsible for their removal would not benefit from an increased production of protease genes. The immune cells would tend to conserve energy and redirect efforts by, for example, turning off protease genes. Thus, various protease genes, including those that appear to be effective in breaking down pre-opioid compounds that are linked to autism (discussed below), may be down-regulated. In fact, DPPIV has been shown to be down regulated in autistics and is currently being used as a diagnostic marker for the disease. In addition, IELs may encourage apoptosis or quiescence of intestinal cells. This cell death or disablement may lead to the xe2x80x9cleakyxe2x80x9d intestinal wall condition often associated with autism and ASD. Down regulation of protease genes and formation of xe2x80x9cleakyxe2x80x9d intestines are examples of the apparently maladaptive response mentioned above.
It is believed that these or other conditions cause the digestive tract of a person with autism to function sub-optimally. Two important pioneers of this work, Reichelt and Shattock, observed a significant correlation between the symptoms of autism and an impaired ability to adequately digest peptides/proteins from dairy (casein) and wheat (gluten). During digestion, pre-opioid type compounds in the diet, typically from casein and gluten, are thought to be activated due to an incomplete breakdown of proteins. These exorphins (i.e., casomorphins and gluteomorphins or gliadinomorphin) are then easily transferred across the lumen of the gut into the circulation where they exert opioid-type action on the brain.
In theory, no enzyme digestion in the body is ever 100% complete. Statistically, some protein or peptide fragments will escape the digestive process and be absorbed. The larger fragments may be transferred across the lumen of the gut via the M-cells and active transport while the smaller fragments may simply diffuse. Coupling these phenomena with the characteristically xe2x80x9cleakyxe2x80x9d intestinal tract of an autistic, it becomes readily apparent how biologically significant quantities of peptides and, more specifically, exorphins can enter the circulation.
The exorphins are recalcitrant to endogenous proteolytic enzyme digestion due to the presence of a proline in the penultimate position of the peptide. The body relies on its own production of dipeptidyl-peptidase IV (DPPIV), in the gut and other cells, for the digestion of exorphins. DPPIV is a serine exo-peptidase that cleaves Xaa-Pro dipeptides from the N-terminus of oligo- and polypeptides. It was first reported as glycylproline naphthylamidase and has been named dipeptidyl aminopeptidase IV or postproline dipeptidyl peptidase IV in early work. As alluded to above, it is suspected that genes which produce DPPIV are down regulated in autistic individuals.
To compensate for the apparent lack of sufficient quantities of DPPlV and to generally rebuild proper functioning of an autistic individual""s intestinal tract with regard to absorption and digestion, different approaches have been employed. Of these, enzyme therapy and probiotic supplementation have been favored and met a degree success. Enzyme therapy has typically been based on supplementation with large amounts of protease from different categories of proteolytic enzymes and these have included acid or carboxyl peptidases, peptidases with both endo- and exo-peptidase activity, and serine, cysteine and zinc protease. More recently exogenic DDPIV from animal (usually cow or pig) and plant source has been utilized. While enzyme therapy has had limited success, it is disadvantageous, amongst other reasons, in that many proteases, including DDPIV, are broken down in the stomach and do not reach the intestines in a functional state.
Probiotic supplementation has focused mainly on trying to rebuild the intestinal wall via a restoration of the naturally occurring bacterial flora. Common intestinal microflora are isolated from the human gut and cultured to form a xe2x80x9cprobiotic culture.xe2x80x9d Two approaches to the treatment of autistic dysbiosis using probiotic cultures have emerged. The first uses a wide variety of organisms and is something of a xe2x80x9cshot-gunxe2x80x9d approach. The second employs a more targeted approach by supplying very large numbers of viable organisms as high as 100 billion/gram. Both approaches have been based on clinically observed and published therapeutic benefits of probiotics and while they have met with limited success relative to no probiotic treatment, they do not adequately treat the syndromes associated with autism, suggesting that exorphin digestion is more than just an issue of microflora composition.
A need thus exists for a more effective manner of breaking down exorphins in the stomach and the intestinal tract of an autistic individual. A need also exists to increase expression of DPPIV and DPPIV like compounds from within an autistic individual""s own body, i.e., overcoming the apparent down regulation of these or related genes. A need further exists for increasing the bioavailability of minerals that facilitate digestion reactions.
Accordingly, it is an object of the present invention to increase expression of DPPIV and/or related compounds in the gut of an individual with autism.
It is another object of the present invention to utilize ingestible materials that modify expression of DPPIV, QPP or another compound whose regulation is beneficial in treating autism.
It is another object of the present invention to provide various formulations that include material that affects the expression or activity of a gene product useful in treating autism and one or more proteases/peptidases for treating autism.
It is also an object of the present invention to provide various formulations for treating autism that include phytase (or phytase-like substances) and protease and/or material that affects the expression or activity of a gene product useful in treating autism.
It is a further object of the present invention to provide various formulations for treating autism that include phospholipids, disaccharidases and/or lipases.
These and related objects of the present invention are achieved by use of a genomeceutical composition and method for treating autism as described herein.
The attainment of the foregoing and related advantages and features of the invention should be more readily apparent to those skilled in the art, after review of the following more detailed description of the invention taken together with the drawings.